Since Kohler and Milstein announced the development of hybridomas that secrete monoclonal antibodies in 1974, numerous in vitro diagnostic assays relying on the specificity of monoclonal antibodies have been comercialized. In vivo applications of monoclonal antibodies, either as therapeutic or as diagnositc agents, are less well developed, however.
Murine monoclonal antibodies are currently used therapeutically in man in a number of clinical situations, usually as immunosuppressive agents, [Cosimi et al., New Engl. J. Med., 305, 308 (1981); Cosimi et al., Transplantation, 32,535 (1981); Chatenoud et al., Transpl. Proc., 15, 643 (1983); Takahashi et al., Lancet, 2, 1155 (1983); and Linch et al., Clin. Exp. Immunol, 51, 133 (1983)] or anti-tumor agents. [Nadler et al., Cancer Res., 40, 3147 (1980); Ritz et al., Blood, 58, 141 (1981); Miller et al., Lancet, 2, 226 (1981); Miller et al., Blood, 58, 78 (1981); Dillman et al., Blood, 59, 1036 (1982), Miller et al.; New Engl. J. Med., 306, 517 (1982); Levy et al., Fed. Proc., 42, 2652 (1983); Miller et al., Blood, 62, 988 (1983); and Sears et al., Lancet, 2, 762 (1982)]. The effect of these treatments is often initially dramatic but, as a rule, rapidly wanes because of two host escape mechanisms: antigenic modulation; i.e., the disappearance of a membrane antigen or receptor induced by binding to its specific ligand, and anti-monoclonal sensitization, the production of host antibodies against the administered monoclonal antibody.
In clinical transplantation it is a common experience that renal allograft recipients treated with conventional xenogeneic anti-lymphocyte sera (that is, sera derived from a species different from the species of the recipient) develop, within the first month of treatment, serological, and sometimes clinical, signs of xeno-sensitization against the injected foreign proteins. Attempts have been made to avoid or attenuate this sensitization by the use of monoclonal antibodies which can be administered in an effective amount at much lower doses than polyclonal antibodies. However, in most of the preliminary clinical trials using murine anti-T cell monoclonal antibodies, the patients did produce antibodies against the murine monoclonals which limited the duration of their biological effectiveness. Moreover, depending upon the treatment protocol used, the production of anti-monoclonal antibodies varied both quantitatively and qualitatively.
In particular, the murine monoclonal antibody OKT3, which is directed against mature human T cells and reacts with the T3 antigen, has been widely used since 1980 as an immunosuppressive agent to prevent or to cure rejection in renal allograft recipients. [Cosimi et al., New Engl. J. Med. 305, 308 (1981)].
In most instances, OKT3 was administered to treat established acute rejection episodes, while in other instances the OKT3 monoclonal antibody was administered prophylactically in order to prevent potential rejection. In an early treatment protocol, the antibody was injected alone (5 mg/day intravenously [IV]) starting on the day of transplantation and then daily for 13 consecutive days. Six patients were included in this trial. As reported in detail in Chatenoud et al., Eur. J. Immunol., 12, 979 (1982), OKT produced three major immunologic effects: (1) a profound initial T cell lymphopenia, appearing within one hour following the first OKT3 injection; (2) antigenic modulation of the OKT3-defined T cell antigen; and (3) an intense xenosensitization present in five of the six treated patients.
The antigenic modulation observed in this study was not associated with the loss of OKT3-immunosuppressive activity. Indeed, in vivo modulated cells were functionally immunoincompetent. [Chatenoud et al., id.; Chatenoud et al., Transplant Proc., 15, 643 (1983)]. However, sensitization represented a major obstacle. Specifically, as soon as significant titers of IgG anti-OKT3 antibodies appeared, the therapeutic effectiveness of OKT3 was completely abrogated. In three of the six patients entered into this protocol, significant titers were detected by Day 9 post-treatment (i.e., four days before the end of the proposed course of treatment).
Although the appearance of these anti-OKT3 antibodies was not associated with serum sickness [Jaffers et al., Transplant. Proc., 15, 646 (1983)], hypersensitivity or anaphylaxis, it necessarily marked the end of the therapeutic effectiveness of the administered monoclonal antibodies.
Also, patient sensitization to the murine monoclonal antibody generally appears between Day 9 and Day 13 of antibody administration and represents an important limitation to antibody treatment.
This sensitization is heterogeneous in specificity. Some antibodies react with "mouse determinants" (anti-isotype antibodies reactive with Fc portions of the murine antibody), while the remainder are anti-idiotype antibodies (reacting with the antigen binding site variable region of the murine antibodies). [Chatenoud et al., Transplant Proc., 15, 643 (1983); Jaffers et al., Transplant. Proc., 15, 646 (1983)].
Once the patient is sensitized, further treatment with the monoclonal antibody is ineffective. Thus, the physician is required to continue the treatment of the patient using high dosages of conventional immunosuppressant drugs. However, these drugs have numerous adverse side effects.
It would be beneficial to be able to prolong the course of treatment using monoclonal antibodies until an allograft rejection is reversed. This would allow the physician to avoid administration of high dosage immunosuppressive drugs that must be used in the absence of monoclonal antibodies and thus the adverse effects of these drugs. The patient would have effective T cell suppression necessary for reversal of the graft rejection and none of the side effects associated with conventional immunosuppressive drugs.
In other cases where monoclonal antibody treatment is contemplated, there may be no acceptable alternative treatment. For example, surgery is an alternative method for determining the size of a tumor. However, repeated surgery is not an acceptable method for determining change in tumor size in response to therapy. In many instances the physician will not be able to closely follow the course of the disease or the patient will be without effective therapeutic treatment once the patient is sensitized to a monoclonal antibody.